The synthesis of sucrose derivatives and improved methods for synthesizing sucrose derivatives is an area of significant research given the abundance and inexpense of sucrose and its suitability as a starting material for making many different biologically and industrially useful compounds.
For example, amino sugars are well known components of antibiotics and antibacterial polysaccharides. Additionally, sucrose derivatives have recently been used to make monomers and polymers from sucrose. See, e.g., Fritschela et al., European Patent 0218150 (1987); Khan et al., Carbohydrate Research (1980), pp. 185-189; and commonly assigned U.S. patent application Ser. No. 07/877,813, filed on May 4, 1992, now U.S. Pat. No. 5,248,747.
Thus, given the known biological and industrial applicability of sucrose derivatives, methods for providing novel sucrose derivatives and methods for their usage would be highly desirable.
Cis-diaminedichloroplatinum (II), cis-DDP, or cisplatin as it is commonly known in the art, is a platinum complex which was first prepared by Alfred Werner in 1893 (Z Anorg. Chem., 1893, 3,267). However, this compound was only of interest to inorganic chemists until Rosenberg and colleagues discovered in 1965 that this complex and several related complexes, specifically cis, cis-diamine-dichloro-trans-dihydroxoplatinum (IV) and cis-cis-trans-diaminetetrachloroplatinum (IV) have the ability to prevent DNA replication in E. coli and that such complexes may be used as antineoplastic agents. (It was found, however, that transplatin or trans-diamine-dichloroplatinum (II), a related complex, does not comprise this activity.)
The structures of these complexes are set forth below. ##STR1##
Because of Rosenberg's discovery, cisplatin and its analogs have been the focus of extensive research. To date, well over 2,000 analogs of cisplatin have been published in the literature.
Cisplatin was approved for clinical usage in 1978 for the treatment of cancer and finds current use in the treatment of cancers, especially solid tumor types, such as testicular cancer, ovarian cancer, cervical cancer, head and neck cancer, and bladder cancer. However, by far its most significant usage in the treatment of testicular cancer since no other antineoplastic compound known behaves as specifically against a particular cancer as does cisplatin against testicular cancer.
Cisplatin, like other biologically active platinum (II) or platinum (IV) complexes, comprises the following generic structure: ##STR2## As depicted in the above structure, the platinum atom is bound to two inert and two labile ligands which are mutually cis. The inert R-NH.sub.2 ligands contain one or more hydrogen atoms which facilitate hydrogen binding to phosphate groups contained in the DNA helix and include, e.g., ammonia, alkylamines, alicycyclic or aromatic amines, or chelating diamines. Suitable labile X groups include chloride, bisulfate, nitrate, water, acetate, oxalate, malonate and the like. Octahedral platinum (IV) complexes may contain only two chloride or hydroxyl ligands axially trans.
As noted, trans(platinum) complexes are not cytotoxic. In addition, bulky complexes containing amines and triamine ligands are not biologically active.
For illustrative purposes, various active, inactive, and second generation cisplatin analogs are depicted below: ##STR3##
Cisplatin and related complexes exert their cytotoxicity by preventing DNA replication. However, it remains unclear as to how such complexes actually enter cells. It has long been assumed that cisplatin enters a cell by passive diffusion. However, this theory has fallen into disfavor recently since extensive evidence exists which indicates that accumulation of the drug may be modulated by means which are incompatible with simple passive diffusion. (See Andrews et al., Cancer Cells, February 1990, Vol. 2, No. 2, pp. 35-43). However, classical proof for an active carrier system is lacking since accumulation is not saturable up to 3 mM cisplatin and cannot be inhibited with structural analogs. (Id. at 35).
Once cisplatin enters a cell, it hydrolyzes to form a diaquodiammino-platinum (II) complex, the substantial portion of which complexes with intracellular proteins. However, about one percent binds to the cellular DNA.
Cisplatin and other related platinum complexes bind to DNA by various means of which the intrastrand mode is both the most prevalent and the most stable. These modes of binding are depicted on the following page. ##STR4##
Of these it is the intrastrand mode which causes kinks to develop in the DNA strand which may prevent DNA replication (if the kinks remain unrepaired). Moreover, it is this prevention of DNA replication which is the mechanism by which cisplatin is eventually lethal to tumor cells.
As discussed supra, cisplatin is very effective in the treatment of some solid tumor type cancers. When used clinically, cisplatin is typically administered intravenously in a hypertonic saline solution or may be intraperitoneally injected directly into a solid tumor site.
However, despite its efficacy in the treatment of cancers, many significant problems remain with the clinical usage of this drug. For example, the cancer cells may develop a resistance to the cisplatin drug, e.g., by (i) developing mechanisms to preclude entry of the drug, (ii) detoxifying the intracellular complexes before they bind to the DNA, or (iii) removing of the platinum bound nucleotides from the DNA by DNA repair mechanisms.
Acquired cisplatin resistance may be reduced but not obviated by various methods including (i) administering increased amounts of the drug, (ii) administering cisplatin in combination with other antineoplastic agents, (iii) administering the drug directly into a tumor site, (iv) inducing hyperthermia, (v) depleting glutathione and other sulfur-rich intracellular proteins, (vi) developing analogs containing multiple cis(platinum) complexes, (vii) binding cisplatin to target specific ligands, or (viii) developing cisplatin complexes containing moieties having different mode or modes of cytotoxity than cisplatin. However, acquired cisplatin resistance is still a significant problem associated with clinical use of this drug.
Another problem with cisplatin is its relative low aqueous and serum solubility. This low solubility can result in low absorption, distribution in the tissues and the precipitation of platinum complexes in the kidneys causing nephrotoxicity and other toxicities including gastrointestinal, reproductive, hematologic, neurotoxicity and ototoxicity. The serum solubility of platinum complexes may be enhanced by oxidizing platinum (II) to platinum (IV) or by complexation to labile ligands such as acetates, oxalates, bisulfates and the like. However, insolubility is still a significant problem which inhibits the clinical efficacy of cisplatin.
Another problem associated with cisplatin is its limited utility. Administration of cisplatin only comprises substantial therapeutic benefit in a few specific human cancers, most particularly testicular cancer.
Yet another problem associated with cisplatin is that it inefficiently binds DNA. As discussed supra, only one percent of the intracellular platinum actually becomes bound to the DNA, and of this only the intrastrand bound platinum results in cytotoxicity.
Recently, various researchers have purported that cisplatin binding to DNA may be enhanced by constructing complexes containing multiple cisplatin moieties. Bis(platinum) complexes have been prepared wherein the cisplatins are bonded with a four to six straight carbon atom linker (Farrell, et al., J. Am. Chem Soc., 1988, Vol. 110, 5018; Farrell et al., Inorganic Chem., 1989, Vol. 28, 3416; Roberts et al., Nucleic Acids Research, 1989, vol. 17, p. 9719; Qu et al., J. Am. Chem. Soc., 1991, Vol. 113, 4851).
Later research by Jones et al. (J. Biol. Chem., 1991, Vol. 266, p. 7101) indicates that endonuclease promoted excision of nucleotides from both DNA strands may in itself be cytotoxic, which lends credence to the belief that his(platinum) complexes will provide better anticancer agents.
However, unfortunately, while bis(platinum) complexes have been prepared of the type below using commercially available 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane, and with chloride or malonate as the labile ligands, significant problems exist with the usage thereof. ##STR5## where n=4=1,4-diaminobutane
n=5=1,5-diaminopentane PA1 n=6=1,6-diaminohexane PA1 and x=chloride or malanate
In particular, all of the complexes prepared using chloride were entirely insoluble which renders them unsuitable for clinical usage. Additionally, the malonate bis(platinum) complexes, while active, displayed delayed toxicity (Farrell et al., J. Med. Chem., 1990, 33, 2174). Thus, it is clear that improved cisplatin complexes free from the above-discussed problems would be highly desirable.